M I C H E L L E C A M E R O N , M D , P T
A S S I S T A NT P R O F E S S O R , D E P A R T M E N T O F N E U R O L O G Y , O H S U
S T A F F N E U R O L O G I S T ,
P O R T L A ND V A M E D I C A L C E N T E R
Multiple Sclerosis for the Primary Care Provider
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 1
Disclosures
Dr. Cameron has received research support from the VA RR&D Service, National MS Society, MS International Federation, Collins Medical Trust, Acorda Therapeutics
Dr. Cameron has received honoraria or consultant fees from Acorda Therapeutics, Teva Neuroscience, Biogen-Idec, Mettler Electronics, DJO Corp and Innovative Neurotronics
Outline
For Multiple Sclerosis (MS)
Describe the following Description and incidence
Typical presentation and progression
PCP work up
Referral – why, when, who
Management – medical, surgical, PCP, specialist, outcomes
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 2
What is MS
CNS disorder (brain, spinal cord, optic nerves)
Symptoms separated in time and space
Complex immune-mediated disorder
Demographics
400,000 patients in USA, 2.5 million worldwide, ~1/700 (total 5000) in Oregon
Typical onset age 20-50 years, average 33-35
Female:male 2-4:1
Caucasians >> other ethnic groups
Variable course of disease
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 3
Pathogenesis
Environmental Factors
Abnormal immunologic response
Genetic Predisposition
Infectious Agent
MS
Gilden Lancet Neurol 2005;4:195-202; Noseworthy NEJM 2000;343:938-952.
Pathophysiology
M S D A M A G E S …
a) Myelin
b) Axons
c) Both
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 4
Demyelination
Axonal Loss
Inflammation
Trapp Curr Opin Neurol 1999;12:295-302; Trapp J Neuroimmunol 1999;98:49-56; Trapp Neuroscientist 1999;5:48-57.
Immunology/Inflammation
Primarily T cell mediated Activation in the periphery
Activated T cells enter the CNS
Reactivation of T cells in the CNS triggers cascade of reactions resulting in CNS damage
B cells, specifics less clear Antigen-presenting cells
Antibody production - ?pathogenetically relevant
Ectopic B-cell follicles in CNS adjoin to pial membrane
Evidence for autoimmune hypothesis
Experimental autoimmune encephalomyelitis (EAE), mouse model
Genetics
Response to immunomodulating and –suppressive agents
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 5
Demyelination
Axonal damage
Trapp, NJEM 1998
Bjartmar, J Neuro Sci 2003
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 6
Diagnosis
Clinical Presentation Additional data needed for MS diagnosis
≥ 2 attacks; objective clinic evidence of ≥ 2 lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack
None
≥ 2 attacks; objective clinical evidence of 1 lesion
DIS by MRI; or await further clinical attack implicating a different CNS site
1 attack; objective clinical evidence of ≥ 2 lesions
DIT by MRI; or await second clinical attack
1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome)
DIS and DIT by MRI
Insidious neurological progression suggestive of MS (PPMS)
1 year of disease progression (retrospectively or prospectively determined)
Plus 2 of the following 3: 1. Evidence for DIS in the brain based on ≥ 1
T2 lesion in characteristic area 2. Evidence for DIS in the spinal cord based
on ≥ 2 lesions in the cord 3. Positive CSF (bands or elevated IgG
index)
2010 Criteria
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 7
2010 McDonald Criteria
Dissemination in space (DIS) ≥ 1 T2 lesions in at least 2 of the following 4 areas of the
CNS Periventricular Juxtacortical Infratentorial Spinal cord
Dissemination in time (DIT) A new T2 and/or Gd enhancing lesion on f/u MRI, with
reference to baseline scan, irrespective of timing of baseline MRI
Simultaneous presence of asymptomatic Gd enhancing and nonenhancing lesions at any time
Brain MRI MS
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 8
Spine MRI
Spine usually not involved in other diseases mimicking MS
MS: PCP work up
H & P (as always!) with a focus on prior neuro sx, time course, distribution, and the neuro exam
MRI brain with and without contrast during relapse
NOT generally spine MRI or CSF
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 9
MS Referral – why, when, who
To be sure of the diagnosis
To help with treatment decisions
Early but not emergent – weeks from onset is generally ok
Neurologist, +/- subspecialist
Clinical Course
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 10
Clinical-isolated Syndrome (CIS)
First demyelinating event
Future risk of definite MS defined by MRI
Baseline
Brain MRI 1 yr 5 yrs 10 yrs 14 yrs 20 yrs
Abnormal
(=single lesion)
30%
65%
83%
88%
82%
Normal
0%
3%
11%
19%
21%
Fisniku Brain 2008:131;808-17
Clinical Course
Which is the most common type of MS?
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 11
MS: Typical presentation and progression
Usually starts with relapsing remitting course of focal neurological symptoms localizable to the CNS or optic nerves e.g. numbness, weakness, vision loss in 1 eye, double vision
Relapses: come on over 1-3 days, last 4-8 weeks and then fully, or almost fully resolve
Other common sx : cognitive, fatigue, heat intolerance, bladder, imbalance
Usually later (10-15 years) in the course, relapses go away but sx gradually progress (secondary progressive MS)
Natural History of MS
1/3 non-ambulatory 20 years after onset
50% unemployed 10-15 years after onset
15-30% have a “benign” course Depends on definition and duration of follow-up
Progressive forms of MS more disabling than RRMS
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 12
MS Therapies
Comprehensive MS Management
Treatment acute relapse
Disease-modifying therapies
Symptom management
Life-style counseling
Smoking cessation
Regular exercise
Albeit inconclusive data at this time, consider supplementation of Vitamin D (fish oil, antioxidants)
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 13
MS Management – medical, surgical, specialist, outcome
Medical – disease modifying therapies to reduce # of relapses and disease progression
Steroids to shorten relapse duration
Surgical – very rare (e.g. biopsy if diagnosis uncertain)
Specialist – recommend DMT; sx management
Outcome – variable, DMTs slow progression during relapsing phase, sx mgmt improves QOL
Disease Modifying Therapy
Favorable impact clinical course and MRI activity
Relapse rate, new/gd+ MRI lesions, brain atrophy,
+/- disability
Poor adherence
Benefit of early treatment
~70% vs 30% reduction annual relapse rate
Acute axonal loss greatest in early stages of disease
Impact on several predictive factors for long-term outcome
CIS w/ abnl MRI: 45-50%/2y reduced conversion to MS
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 14
FDA Approved MS disease modifying therapies - 2013
Betaseron 1993
Avonex 1996
Copaxone 1997
Mitoxantrone 2000
Rebif 2002
Natalizumab 2006
Fingolimod 2010
Teriflunomide 2012
BG-12 ?2013
Treatment of acute relapses
IV methlyprednisolone, 1g IV x 3-5 days
Shortens relapse duration
No effect on time to next relapse, long term disability
Weigh risks and benefits
Consider if this is a “pseudo-relapse”
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 15
PCP Role in MS Management
Initiate diagnostic work up
Monitor for drug AEs, e.g. CBC, LFTs;
Sx management e.g. pain, bladder, bowel
Steroids for relapses Solumedrol 1g IV daily X 3-5 days
Shortens relapse but does not change outcome
Evaluate for psuedo relapse
Symptom management
Essential for QOL
Cognition
Vision
Headaches
Pain
Weakness
Fatigue
Reduced mobility
Bladder
Bowel
Sexual function
Spasticity
Social
Work
Home
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 16
MS and pregnancy - Rate of Relapse
1 2 3 4 1 2 3 1 2 3 4
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
Delivery
Confavreux. NEJM. 2003; 339(5): 285
Rel
ap
ses
per
Wo
ma
n p
er Y
ear
Trimesters before
Pregnancy
Trimesters during
Pregnancy
Trimesters after
Pregnancy
Summary
MS is a CNS disease with variable progressive course
Therapy includes relapse management, disease modifying interventions and symptom management
There are a number of DMT available for RRMS
Newer therapies appear to be more effective but carry increased risk
April 5, 2013
NW PADRECC - Parkinson's Disease Research, Education, and Clinical Center Portland VA Medical Center www.parkinsons.va.gov/northwest 17
Summary
Diagnosis – 2 clinical events separated in time and space, supportive MRI, +/- ancillary tests, rule out other possible explanations
Management – DMT, relapses, symptoms
The future is bright – many new treatments on the horizon
QUESTIONS